Efzimfotase alfa missed significance on the six-minute walk test in adolescents and adults, while the FDA review of the therapy proceeds toward 2027.
Efzimfotase alfa, an investigational enzyme replacement therapy from Alexion, AstraZeneca Rare Disease, missed statistical significance on the primary endpoint of the phase 3 HICKORY trial in hypophosphatasia (HPP). At week 25, adolescents and adults treated with the drug walked 17.05 meters farther than those on placebo on the six-minute walk test (p=0.1675), according to results presented October 11 in Boston.¹
The FDA is reviewing a biologics license application for the drug under priority review, with an action date expected in the first half of 2027.² The filing also draws on two pediatric trials.²
Kathryn Dahir, MD, of Vanderbilt Health, the trial’s lead investigator, said: “For adolescents and adults, the chronic and progressive disease burden of HPP can have far-reaching impact on physical function and emotional wellbeing, potentially impairing people’s ability to live independently, form connections and sustain employment. These results from the HICKORY Phase III trial signal benefits across multiple clinically relevant endpoints and represent an important step toward potentially bringing this advanced enzyme replacement therapy to a broad range of people who may benefit.”
HICKORY randomized 124 patients from 17 countries 2:1 to efzimfotase alfa or placebo, given by subcutaneous injection every two weeks for 24 weeks.¹ Participants had not previously received Strensiq (asfotase alfa) and had walk distances below 85% of predicted values.¹
The company attributes the missed primary endpoint largely to better-than-expected results in the adult-onset placebo group, but the release provides no data to test that explanation independently.¹ Subgroups diverged, as patients with pediatric-onset disease showed a 35.6-meter walk-test difference versus placebo (nominal p=0.0386), while adult-onset patients showed −2.70 meters (nominal p=0.8764).¹
In a post hoc analysis, 45.2% of treated patients reached a clinically meaningful walk-distance gain, compared with 30.0% on placebo (odds ratio, 2.50; 95% confidence interval, 1.06-5.91).¹ A fatigue measure favored treatment by 5.74 points (nominal p=0.0016).¹
Because the primary endpoint missed, these findings are best read as exploratory. Patients in the open-label extension improved through week 49, though that phase has no placebo comparator.¹
HPP is a rare inherited metabolic disease caused by deficient alkaline phosphatase activity. A registry analysis of 398 adults found that pain, muscular and constitutional manifestations are common regardless of age at onset, alongside skeletal signs.³
Because asfotase alfa is indicated for pediatric-onset disease in most countries, many adults reported to have adult-onset disease typically go untreated.³ The registry is sponsored by Alexion.
The company cites a US prevalence study estimating that about 80% of people with HPP are adults.¹
Asfotase alfa received US approval in 2015 and is dosed three or six times weekly.⁴ Efzimfotase alfa combines the catalytic domain of human tissue-nonspecific alkaline phosphatase with an immunoglobulin Fc domain and a bone-targeting peptide.
It also carries a point mutation intended to raise enzymatic activity and two removed glycosylation sites intended to improve pharmacokinetics.⁴ A phase 1 study in 15 adults found acceptable safety and sustained reductions in disease biomarkers, though the authors, several of them Alexion employees, noted its small size and lack of a control group.
Dahir was the lead author of that study and has disclosed consulting and research funding relationships with Alexion.⁴ In a pooled analysis of two of the phase 3 trials, the company reports an annualized injection site reaction rate five times lower than that seen in Strensiq’s registrational trials during the first 24 weeks.¹
That is a cross-trial comparison, not a head-to-head result.
The primary miss, the post hoc and subgroup analyses, and the absence of detailed safety tables in the release limit what can be concluded. Registrational data from the pediatric trials will carry much of the filing.
Submissions are also under review in Japan and other markets.²
Gianluca Pirozzi, senior vice president and head of development, regulatory and safety at Alexion, said: “The HICKORY Phase III trial builds on the positive results from the MULBERRY and CHESTNUT trials and demonstrates the potential of efzimfotase alfa to address the diverse and complex clinical manifestations of HPP across a broad population of patients. With the recently granted Priority Review in the US, we look forward to bringing this potential new therapy with favorable tolerability and dosing convenience to the HPP community, including those with limited treatment options.”
Whether the FDA weighs the adult data as supportive remains an open question until its decision.
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